1
Development of catalysts for asymmetric hydrogenation Katherine Jolley, Rina Soni, Guy Clarkson and Martin Wills Department of Chemistry, The University of Warwick, Coventry, CV4 7AL, UK A key development within our research group has been the development of tethered ruthenium catalyst (B) 4a which offers greater stability and enhanced activity for asymmetric transfer hydrogenation (ATH) of ketones than Noyoris complex (A) as shown in Figure 2. Previously much work has focussed on ATH with tethered catalysts 4 rather than APH using hydrogen gas with only one reported example of the application of catalyst B to APH shown in Figure 5. 5 We recently reported the application of tethered catalysts to the APH of ketones and aldehydes. 6 Asymmetric hydrogenation of carbonyl compounds is an important process for the production of enantiomerically pure products. One of the most successful and widely used series of catalysts for this process are ruthenium catalysts of type A first developed by Noyori in 1995. 1 The catalysts were initially used for asymmetric transfer hydrogenation (ATH) of ketones 2 and later for asymmetric pressure hydrogenation (APH) of ketones with H 2 gas 3 as shown below in Figure 1. Figure 1. ATH 2 (left) and APH 3 (right) of ketones using Noyoris complex A. A Figure 2. ATH (left) 4 and APH 5 (right) of ketones using tethered complex B. B Introduction Application of 3C tethered catalysts to APH of ketones Catalyst B demonstrates high activity and enantioselectivity for the APH of a range of ketones, tolerating aryl substitutions, bicyclic ketones, a range of α-substituents and also aliphatic ketones. 6 Use of MsDEPEN derived catalyst C required 50 bar H 2 pressure to achieve full conversion in the same time as the TsDPEN catalyst B (results in green), however the enantiomeric excess of the alcohol products obtained was often slightly lower than with catalyst B. Figure 3. APH of ketones with 3C-tethered ruthenium catalysts B (black) and C (green). 6 Mechanism of ATH and APH of ketones Noyori has reported separate mechanisms for ATH and APH using this type of catalyst. 7 ATH proceeds via loss of HCl with base, whilst APH proceeds via an initial ionisation to remove the chloride forming a cationic complex which then interacts with the H 2. It has been reported that he ionisation process and catalytic activity of the catalyst can be increased with use of a Ru-OTf complex rather than Ru-Cl. 7 Figure 4. Mechanism of ATH (red) and APH (blue) of ketones. 7 APH with a tethered ruthenium iodide catalyst We proposed that an iodo derivative for the tethered catalyst (D) may allow for a more active catalyst, undergoing the initial ionisation step more readily than the original chloro catalyst (B). CatalystS/C Temp. (°C) Time (hr.) Conv. (%) Ee (%) (S,S)-B500/1601699.893.2 (S) (S,S)-D500/1601656.592.7 (S) (S,S)-B1000/1601621.086.6 (S) (S,S)-D1000/160164.675.3 (S) (S,S)-B2000/16064.539.886.3 (S) (S,S)-D2000/16064.545.286.7 (S) The tethered iodo catalyst (D) was prepared in 1 step from its chloro counterpart (B) but was found to be less active than the chloro derivative for APH of acetophenone. Over long reaction times (64.5 hr.) however, catalyst D gave a slightly improved conversion compared to catalyst B suggesting it has enhanced stability and a longer lifetime in the reaction than B. Figure 5 shows the iodo catalyst (D) to be approximately half as active as the chloro derivative (B). The iodo catalyst requires approximately 2 hours for catalyst activation and a constant reaction rate to be achieved whereas the chloro catalyst requires only 1 hour. Scheme 1. Synthesis and X-Ray structure of iodo catalyst D. D Table 1. APH of acetophenone with 3C-tethered catalysts B and D. Figure 5. Reaction rates for APH of acetophenone with catalyst B and D. (S,S)- tethered RuCl catalyst B (S,S)- tethered RuI catalyst D Achiral tethered catalyst F for APH of aldehydes 4-carbon tethered catalyst E for APH of ketones Catalyst E showed good scope for a range of ketones. In terms of activity, the conversions equalled those obtained with catalyst B, however the ees were generally lower than with catalyst B, showing the 4C catalyst to be less stereoselective than its 3C counterpart. Tethered catalysts are also active for APH of aldehydes, however initial studies on the APH of benzaldehyde using the achiral-3C- tethered catalyst F gave formation of dimethoxymethyl-benzene in addition to benzyl alcohol. 6 SubstrateSolvent Time (hr.) Conversion to products (%) 10:90 H 2 O:MeOH 16 99.5 10:90 H 2 O:MeOH 16 99.6 10:90 H 2 O:MeOH 16 99.8 10:90 H 2 O:MeOH 16 94.8 2.8 10:90 H 2 O:MeOH 24 96.1 3.5 0.3 The addition of 10% water to the MeOH solvent was found to eliminate the formation of the dimethoxy product. APH of a range of aldehydes using catalyst F gave good conversions to the desired alcohol product and also demonstrated high levels of chemoselectivity for the hydrogenation of the C=O bond over C=C and NO 2 groups. 6 F Scheme 2. Preparation of 4C-tethered catalyst E. The 4C-tethered catalyst E was prepared from 4-phenylbutanol in 5 steps as shown in Scheme 2. The catalyst was then applied to the APH of a range of ketones as shown below. Figure 6. APH of ketones with 4C-tethered catalyst E. D Table 2. APH of aldehydes with achiral 3C-tethered catalyst F. Conclusions and AcknowledgementsReferences Tethered catalysts have been successfully applied to APH of ketones and aldehydes. The 3C-tethered RuCl catalyst B proved to be the most active and enantioselective catalyst with the iodo derivative showing reduced activity and the MsDPEN and 4C catalysts showing reduced enantioselectivity. The achiral catalyst E demonstrated good activity and chemoselectivity for APH of aldehydes. Work continues with the development of new tethered catalysts for APH of carbonyl compounds and also with the development of new, more efficient methods of synthesis for tethered catalysts. I would like to thank Martin Wills, the Wills Group, Guy Clarkson and collaborators at Johnson Matthey Catalysis and Chiral Technologies for their help during this project. Funding was from the EPSRC (EP/G036993/1). 1.S. Hashiguchi, A. Fujii, J. Takehara, T. Ikariya and R. Noyori, J. Am. Chem. Soc. 1995, 117, 7562. 2.A. Fujii, S. Hashiguchi, N. Uematsu, T. Ikariya and R. Noyori, J. Am. Chem. Soc. 1996, 118, 2521. 3.T. Ohkuma, K. Tsutsumi, N. Utsumi, N. Arai, R. Noyori and K. Murata, Org. Lett. 2006, 9 255. 4.a) A. Hayes, D. Morris, G. Clarkson and M. Wills, J. Am. Chem. Soc. 2005, 127, 7318. b) D. Morris, A. Hayes and M. Wills, J. Org. Chem. 2006, 71, 7035. 5.D. Morris, and M. Wills, Chem. Oggi. 2007, 25 Catalysis Supplement, 11. 6.K. Jolley, A. Zanotti-Gerosa, F. Hancock, A. Dyke, D. Grainger, J. Medlock, H. Nedden, J. Le Paih, S. Roseblade, A. Seger, V. Sivakumar, I. Prokes, D. Morris and M. Wills, Adv. Synth. Catal. 2012, 354, 2545. 7.T. Ohkuma, N. Utsumi, K. Tsutsumi, K. Murata, C. Sandoval and R. Noyori, J. Am. Chem. Soc. 2006, 128, 8724. C 50 C 16hr. 99.9%, 91.7% (R) ee 16hr. 99.9%, 91.1%(R) ee 16hr. 99.6%, 91.1% (R) ee 16hr. 99.8%, 9105%(R) ee 16hr. >99.9%, 88.2% (R) ee 16hr. 99.9%, 85.5%(R) ee 24hr. 94.0%, 99.2% (R) ee 48hr. 99.9%, 97.8%(R) ee 48hr. >99.9%, 66.8% (S) ee 48hr. 94.5%, 46.7%(S) ee Scheme 3. Hydrogenation of benzaldehyde.